There is growing consensus that optimizing treatment outcomes for substance use disorders may be achieved through careful integration of pharmacologic and psychosocial interventions. Working closely with Project 3 for the identification of compounds, the proposed project will assess the ability of select pharmacotherapeutic agents to augment the therapeutic effects of a cue exposure intervention for methamphetamine (METH) dependence and to preliminarily assess impact on measures of cognitive functioning. D-cycloserine (DCS), a partial glutamate agonist facilitates associative learning, is one agent likely to be explored and has been chosen as the prototype for this application. The specific aims are: 1. To develop a set of environmental cues specific to METH use;2. To investigate the ability of the METH-specific cues to elicit craving and physiological reactivity in METH-dependent individuals;3. To explore the impact of DCS on response to METH-related cues;and 4. To preliminarily explore the relationship of cognitive function to DCS response in METH dependent individuals. We will initially develop methamphetamine cues through conducting interviews with METH dependent individuals and pilot testing to assess the ability of the cues developed to provoke craving and physiologic response. In vivo, picture and video cues will be developed within the first six months. In parallel, a Virtual Reality METH cue environment will be developed to be used in future studies. After a satisfactory set of cues has been developed, METH-dependent individuals will be recruited to receive either DCS or a placebo prior to each of two, one-hour exposure sessions in which drug use and other drug-related stimuli will be presented using in vivo and video cue presentation. Multiple assessments of craving and physiologic reactivity will be obtained during and after the cue exposure sessions and during an unmedicated test session one-month after the second cue exposure session. The primary outcome measures will be subjective (craving, desire to use) and physiologic (heart rate, skin conductance) responses to METH cues. In summary, this pilot project will begin with the development of METH-related environmental cues to be used both in this project and Project 2. Guided by the findings of Project 3, the use of innovative pharmacologic approaches to the treatment of METH dependence through the facilitation of extinction of responses to METH conditioned cues will be explored. The impact of pharmacologic agents on cognitive function in METH dependent individuals will also be preliminarily explored. Through working closely with the other center studies, methodology will be developed and pilot data generated to guide a P50 application.